1 **Annex 4. Item 5.1. – Chapter 1.1.5. Quality management in veterinary testing laboratories**

###### 2 MEETING OF THE WOAH BIOLOGICAL STANDARDS COMMISSION

3 **Paris, 4–8 September 2023**

4

5

6	C H A P T E R 1. 1.5 .

# 7	QU AL IT Y M ANA G EM ENT IN V ET ER INAR Y

8	**T EST ING LAB OR AT OR IES**

9	**SUMMARY**

10 *Valid laboratory results are essential for diagnosis, surveillance, and trade. Such results are ~~achieved by the~~*

11 *~~use~~assured through implementation of ~~good~~a management ~~practices, valid~~system that supports accurate*

12 *and consistent test and calibration methods~~, proper techniques, quality control and quality assurance, all~~*

13 *~~working together within a quality management system~~. Laboratory quality management includes technical,*

14 *managerial, and operational elements of ~~testing~~performing, interpreting and ~~the interpretation of~~reporting*

15 *test results. A quality management system enables the laboratory to demonstrate both competency and an*

16 *ability to generate consistent technically valid results that meet the needs of its customers. ~~The need for~~*

17 *Mutual recognition and acceptance of test results for international trade, and the ~~acceptance~~accreditation*

18 *of tests to international standards such as ISO/IEC*25*17025~~:2005~~*(*General Requirements for the*

19 *Competence of Testing and Calibration Laboratories*) (*ISO/IEC, ~~2005~~2017b*) *requires ~~good~~suitable*

20 *laboratory quality management systems. This chapter is not intended to reiterate the requirements of*

21 *ISO/IEC 17025, nor has it been endorsed by accreditation bodies. Rather, it outlines the important issues*

22 *and considerations a laboratory should address in the design and maintenance of its quality management*

23 *system, ~~whether or not it has been formally accredited~~regardless of formal accreditation status. Chapter*

24 *1.1.1*Management of ~~veterinary diagnostic laboratories *gives an introduction to*~~veterinary diagnostic

25 laboratories *introduces the components of governance and management of veterinary laboratories that are*

26 *necessary for the effective delivery of diagnostic services, and highlights the critical elements that should be*

27 *established as minimum requirements.*

## 28	A. KEY CONSIDERATIONS FOR THE DESIGN AND MAINTENANCE OF A

29	**LABORATORY QUALITY MANAGEMENT SYSTEM**

30 To ensure that the quality management system is appropriate and effective, the design must be carefully ~~thought out~~

31 planned and, where accreditation is sought, must address all criteria of the appropriate quality standard. The major

32 ~~categories of~~ considerations and ~~the~~their associated key issues and activities~~within each of these categories~~ are outlined

33 in the following eight sections of this chapter.

1 ISO/IEC: International Organization for Standardization/International Electrochemical Commission.

#### 34 1.	The work, responsibilities, and goals of the laboratory

35 Many factors affect the necessary elements and requirements of a quality management system~~. These factors include~~,

36 including:

37 i)	Type of testing ~~done~~performed, e.g. research versus diagnostic work;

38 ii)	Purpose and requirements of ~~the~~test results, e.g. ~~for~~import~~or~~/export quarantine testing, surveillance, emergency

39 disease exclusion, declaration of freedom from disease post-outbreak;

40 iii)	Potential impact of a questionable~~or~~, erroneous or unfavourable result, e.g. detection of foot and mouth disease

41 (FMD) in an FMD-free country;

42 iv)	~~The tolerance level of~~Risk and liability tolerance, e.g. vaccination ~~vs~~versus culling~~or~~/slaughter;

43 v)	Customer ~~needs (~~requirements, e.g. sensitivity and specificity~~of the test method~~, cost, turnaround time, ~~strain or~~

44 ~~genotype~~ level of characterisation~~), e.g. for surveillance, or declaration of freedom after outbreak~~;

45 vi)	~~The role of the laboratory~~Role in legal work or in regulatory programmes, e.g. for disease eradication and declaration

46 of disease freedom to the WOAH;

47 vii)  ~~The role of the laboratory~~Role in assisting with, confirming, or overseeing the work of other laboratories (e.g. as a

48 reference laboratory);

49 viii) Business goals~~of the laboratory~~, including the need for any third-party recognition or accreditation.

#### 50 2.	Standards, guides, and references

51 The laboratory should ~~choose reputable and accepted~~follow globally recognised standards ~~and guides~~to assist in

52 designing the quality management system. For laboratories seeking ~~accreditation~~formal recognition of testing competency,

53 and for all WOAH Reference Laboratories, the use of ISO/IEC 17025 (ISO/IEC, ~~2005~~2017b) or equivalent ~~will be~~is

54 essential. This standard includes specifies managerial and technical requirements and accredited laboratories~~that are~~

55 ~~compliant~~ are regarded as competent. Further information on standards may be obtained from the national standards body

56 of each country, from the International Laboratory Accreditation Cooperation (ILAC) 26, and from accreditation bodies, ~~e.g.~~

57 ~~the National Association of Testing Authorities (NATA), Australia, the United Kingdom Accreditation Service (UKAS), the~~

58 ~~American Association for Laboratory Accreditation (A2LA), etc~~. Technical and international organisations such as AOAC

59 International (The Scientific Association Dedicated to Analytical Excellence; formerly the Association of Official Analytical

60 Chemists) and the International Organization for Standardization (ISO) publish useful references, guides, application

61 documents and standards that supplement the general requirements of ISO/IEC 17025. Other relevant documents may

62 include guides and application documents providing interpretative criteria and recommendations for the application of

63 ISO/IEC	17025	in	the	field	of	veterinary	testing	for	both	applicant	and	accredited	facilities,	e.g.

64 ~~https://www.nata.com.au/phocadownload/spec-criteria-guidance/animal-health/Animal-Health-ISO-IEC-17025-~~

65 Appendix.pdfhttps://nata.com.au/files/2021/05/Animal-Health-ISO-IEC-17025-Appendix-effective-March2021.pdf;

66 Newberry & Colling, 2021.

67 The ISO International Standard 9001 (ISO, 2015)~~, is a certification standard~~specifies the requirements for quality

68 management systems and while it may be a useful ~~supplement~~framework to ~~a~~underpin a laboratory quality system,

69 fulfilment of its requirements does not ~~necessarily ensure or imply~~assure technical competence (in the areas listed in

70 Section 3 *Accreditation*). Conformance to the requirements of ISO 9001 is assessed by a certification body that is

71 accredited ~~to undertake such assessments~~by the national accreditation body to undertake such assessments. When a

72 laboratory meets the requirements of ISO 9001*,*the term *registration*or *certification*is used to indicate conformity, not

73 *accreditation*.

74 With the advent of stronger alliances between medical and veterinary diagnostic testing under initiatives such as “One

75 Health”, some laboratories may ~~wish to~~choose to follow other ISO standards such as ISO 15189 Medical Laboratories –

76 Requirements for Quality and Competence (ISO/IEC, ~~2012), which include~~2022), for testing of human samples, e.g. for

77 zoonotic diseases. It should be noted that for veterinary laboratories, limited availability of suitable material may render

78 validation difficult; under these circumstances it is necessary to highlight the limited validation status when reporting results

79 and their interpretation (Stevenson *et al.,*2021).

#### 80 3.	Accreditation

81 If ~~the laboratory decides to proceed with~~formal recognition of ~~its~~a laboratory’s quality management system and testing,

82 ~~then~~ is sought, third party verification of its conformity with the selected standard(s) ~~will be~~is necessary. ILAC has published

83 specific requirements and guides for laboratories and accreditation bodies. Under the ILAC system, ISO/IEC 17025 is to

2 ILAC: The ILAC Secretariat, PO Box 7507, Silverwater, NSW 2128, Australia; http://ilac.org/

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84 be used for laboratory accreditation of testing or calibration activities. Definitions regarding laboratory accreditation may

85 be found in ISO/IEC International Standard 17000: Conformity Assessment – Vocabulary and General Principles (ISO/IEC,

86 ~~2004a~~2020). Accreditation is ~~tied to~~dependent on demonstrated competence, which ~~is~~encompasses significantly more

87 than having and following documented procedures. Providing a competent and customer-oriented service also ~~means that~~

88 ~~the laboratory~~requires:

89 i)	Adequate facilities and environmental controls;

90 ii)	~~Has~~Appropriately qualified and trained personnel with a depth of technical knowledge commensurate with

91 appropriate level of authority;

92 iii)	~~Has appropriate~~Equipment ~~with planned~~that is appropriately verified and managed in accordance with the relevant

93 maintenance and calibration schedule;

94 ~~iv)	Has adequate facilities and environmental control;~~

95 ~~v)	Has procedures and specifications that ensure accurate and reliable results;~~

96 ~~vi)	Implements continual improvements in testing and quality management;~~

97 ~~vii)  Can assess the need for and implement appropriate corrective or preventive actions, e.g. customer satisfaction;~~

98 ~~viii) Accurately assesses and controls uncertainty in testing;~~

99 ix)	Appropriate sample and materials management processes;

100 x)	~~Has~~ Technically valid and validated test methods, procedures and specifications~~that are~~, documented in accordance

101 with the requirements of the applicable standard or guidelines, e.g. Chapter 1.1.6 *Principles and methods of validation*

102 *of diagnostic assays for infectious diseases*~~and~~*,*chapters 2.2.1 to 2.2.8 *Recommendations for validation of diagnostic*

103 *tests*and Special Issue of the *Scientific and Technical Review*(2021)27;

104 xi)	~~Demonstrates~~Demonstrable proficiency in the applicable test methods ~~used~~(e.g. by regular participation in

105 proficiency ~~tests on a regular basis~~testing schemes);

106 xii)  Accurate assessment and control of the measurement of uncertainty in testing;

107 xiii) Good documentation practices, e.g. ALCOA+ principles (i.e. Attributable, Legible, Contemporaneous, Original,

108 Accurate, Complete, Consistent, Enduring, Available);

109 xiv) Non-conformance management process, including detection, reporting, risk-assessment and implementation of

110 effective corrective and preventive actions;

111 xv)  Complaints management;

112 xvi) Adequate control of data and information;

113 xvii) Appropriate reporting and approval process;

114 xviii) Culture of continual improvement.

115 xix) Has demonstrable competence to generate technically valid results.

#### 116 4.	Selection of an accreditation body

117 To facilitate the acceptance of the laboratory’s test results for trade, the accreditation standard used must be recognised

118 by the international community and the accreditation body recognised as competent to accredit laboratories. Programmes

119 for the recognition of accreditation bodies are, in the ILAC scheme, based on the requirements of ISO/IEC International

120 Standard 17011: Conformity Assessment – General Requirements for Accreditation Bodies Accrediting Conformity

121 Assessment Bodies (ISO/IEC, ~~2004b~~2017a). Information on recognised accreditation bodies may be obtained from the

122 organisations that recognise them, such as the Asia-Pacific Accreditation Cooperation (APAC), the Inter-American

123 Accreditation Cooperation (IAAC), and the European Co-operation for Accreditation (EA).

124 Accreditation bodies may also be signatory to the ILAC and regional (e.g. APAC) mutual recognition arrangements (MRAs).

125 These MRAs are designed to reduce technical barriers to trade and further facilitate the acceptance of a laboratory’s test

126 results in foreign markets. Further information on the ILAC MRA may be obtained from the www.ilac.org.

#### 127 5.	Determination of the scope of the quality management system or of the laboratory’s

128 **accreditation**

3  Available at: https://doc.woah.org/dyn/portal/index.xhtml?page=alo&aloId=41245

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129 The scope of the quality management system should ~~cover all areas of activity affecting all~~ include all activities that impact

130 testing ~~that is done at~~performed by the laboratory. Whilst only accredited laboratories are obliged to meet ~~the~~ requirements

131 of the relevant standard~~as detailed below, these~~, the guiding principles should be considered best practise and are relevant

132 to all testing laboratories.

133 ~~Laboratories accredited~~A laboratory’s accreditation to ISO/IEC 17025 ~~have~~includes a ~~specific~~ list of ~~those~~accredited tests

134 ~~that are accredited, called~~, referred to as the schedule or scope of accreditation~~or the scope. Veterinary testing facilities~~

135 include government and private facilities, veterinary practices, university veterinary schools, and other laboratories for the

136 ~~testing of animals and animal products for the diagnosis, monitoring and treatment of disease~~. In principle, if new testing

137 methods are introduced these must be assessed and accredited before they can be added to the scope, however a flexible

138 scope can be implemented that assesses the laboratory as competent to add tests to scope, which are then formally added

139 at the next accreditation visit. ~~The quality management system should ideally cover all areas of activity affecting all testing~~

140 ~~that is done at the laboratory. However, it is up to the laboratory to decide which tests are to be accredited and included in~~

141 ~~the scope.~~If an accredited laboratory also offers ~~unaccredited~~non-accredited tests, these must be clearly indicated as

142 such on any reports that claim or ~~make~~reference ~~to~~accreditation. ~~Factors~~It is ultimately the decision of the laboratory to

143 decide which tests require inclusion in the scope of accreditation, and factors that might affect ~~the laboratory’s choice of~~

144 ~~tests for scope of accreditation~~this decision include:

145 ~~i)	The impact of initial accreditation on resources within a given deadline;~~

146 ii)	Associated risks and opportunities;

147 iii)	Initial investment required (e.g. time, resources);

148 iv)	~~A~~Contractual requirement for accredited testing (e.g. for international trade, research projects);

149 v)	~~The~~Importance of the test and the potential impact of an incorrect result;

150 vi)	The cost of maintaining an accredited test versus frequency of use;

151 vii)  Availability of personnel, facilities and equipment;

152 viii) Availability of appropriate materials and reference standards (e.g. ~~standardised~~reagents, internal quality control

153 ~~samples~~controls, reference cultures)~~and~~

154 ix)	Access to proficiency testing schemes;

155 x)	The quality ~~assurance~~control processes necessary for materials, reagents and media;

156 xi)	The validation status, e.g. access to field samples from infected and non-infected animals, technical complexity and

157 reliability of the test method;

158 xii)  ~~The~~Potential for subcontracting of accredited tests.

#### 159 6.	Quality assurance, quality control and proficiency testing

160 Quality assurance (QA) is the ~~part~~element of quality management focused on providing confidence that ~~quality~~defined

161 requirements ~~will be~~are fulfilled. The requirements may be internal or defined in an accreditation or certification standard.

162 QA is process-oriented and ~~ensures~~provides the ~~right things are being done in the right way~~appropriate inputs to prevent

163 problems arising.

164 Quality control (QC) is the systematic and planned monitoring of outputs to ensure ~~the~~minimum levels of quality

165 requirements have been met. For a testing laboratory, this ~~is to ensure test processes~~ensures tests are ~~working correctly~~

166 performing consistently and reliably, and results are within ~~the expected~~acceptable parameters and limits. QC is ~~test~~

167 ~~orientated and ensures the~~results~~are as expected~~-oriented and ensures detection of any problems that arise.

168 Proficiency testing (PT), sometimes referred to as external quality assurance ~~or~~(EQA), is the ~~determination~~assessment

169 of a laboratory’s performance ~~by~~when testing a standardised panel of specimens of undisclosed content. Ideally, PT

170 schemes should be ~~run~~managed by an external independent provider. Participation in proficiency testing schemes enables

171 the laboratory to assess and demonstrate ~~the~~their testing reliability ~~of results by~~in comparison with ~~those from~~other

172 participating laboratories.

173 All laboratories should, where possible, participate in external proficiency testing schemes appropriate to ~~their testing.~~

174 ~~Participation~~the suite of tests provided; participation in such schemes is a requirement for accredited laboratories. This

175 provides an independent assessment of the testing methods used ~~and~~as well as the level of staff competence. If such

176 schemes are not available, valid alternatives may be used, such as ring trials organised by reference laboratories, inter-

177 laboratory testing, use of certified reference materials or internal quality control samples, replicate testing using the same

178 or different methods, retesting of retained items, ~~and~~or correlation of results for different characteristics of a specimen.

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179 Providers and operators of proficiency testing programmes should be accredited to ISO/IEC 17043 – Conformity

180 Assessment – General Requirements for Proficiency Testing (ISO/IEC, 2010).

181 Proficiency testing material from accredited providers ~~has been~~is well characterised and any spare material, once the

182 proficiency testing has been completed, can be useful to demonstrate staff competence or for test validation. Information

183 about selection and use of reference samples and panels is available in Chapter 2.2.6 *Selection and use of reference*

184 *samples and panels*. Proficiency testing and reproducibility scenarios are described by Johnson & Cabuang (2021) and

185 Waugh & Clark (2021), respectively.

#### 186 7.	Test methods

187 ISO/IEC 17025 requires the use of appropriate test methods and has requirements for their selection, development, and

188 validation to ~~show~~demonstrate fitness for purpose.

189 This *Terrestrial Manual*provides recommendations on the selection of test methods for trade, diagnostic and surveillance

190 purposes in the chapters on specific diseases. Disease-specific chapters include, or will include in the near future, a table

191 of the tests available for the disease, graded against the test’s fitness for purpose; these purposes are defined in the WOAH

192 Validation Template (chapter 1.1.6)*,*which identifies six main purposes for which diagnostic tests may be carried out. The

193 table is intended ~~to be~~as a general guide to test application~~.~~; the fact that a test is recommended does not necessarily

194 mean that a laboratory is competent to perform it. The laboratory quality system should incorporate provision of evidence

195 of competency.

196 In ~~the~~veterinary ~~profession~~laboratories, other standard methods (published in international, regional, or national

197 standards) or fully validated methods (having undergone a full collaborative study and that are published or issued by an

198 authoritative technical body such as the AOAC International) may be preferable to use, but ~~may~~not ~~be~~available. Many

199 veterinary laboratories develop or modify methods, and most laboratories have test systems that use non-standard

200 methods, or a combination of standard and non-standard methods. In veterinary laboratories, even with the use of standard

201 methods, some in-house evaluation, optimisation, or validation is generally ~~must be done~~required to ensure valid results.

202 Customers and laboratory staff must have a clear understanding of the performance characteristics of the test, and

203 customers should be informed if the method is non-standard. Many veterinary testing laboratories will therefore need to

204 demonstrate competence in the development, adaptation, verification and validation of test methods.

205 This *Terrestrial Manual*provides more detailed and specific guidance on test selection, optimisation, standardisation, and

206 validation in chapter 1.1.6. ~~Chapter 1.1.6 refers to~~ chapters 2.2.1–2.2.8*~~Recommendations for validation of diagnostic tests~~*

207 ~~that~~ deal with the development and optimisation of fundamentally different assays such as antibody, antigen and nucleic

208 acid detection~~s~~ tests, measurement uncertainty, statistical approaches to test validation, selection and use of reference

209 samples and panels, validation of diagnostic tests for wildlife, and comparability experiments after changes in a validated

210 test method.

211 The following are key test method issues for those involved in the quality management of the laboratory.

##### 212 7.1.	Selection of the test method

213 Valid results begin with the selection of a test method that meets the needs of the laboratory’s customers in

214 addressing their specific requirements (fitness for purpose). Some issues relate directly to the laboratory, others to

215 the customer.

###### 216 7.1.1. Considerations for the selection of a test method

217 i)	International acceptance;

218 ii)	Scientific acceptance;

219 iii)  Appropriate or current technology;

220 iv)  Suitable performance characteristics (e.g. analytical and diagnostic sensitivity and specificity,

221 repeatability, reproducibility, isolation rate, limits of detection, precision, trueness, and

222 uncertainty);

223 v)	Suitability of the test in the species and population of interest;

224 vi)  Sample type (e.g. serum, tissue, milk) and its expected quality or state on arrival at the laboratory;

225 vii) Test target (e.g. antibody, antigen, live pathogen, nucleic acid sequence);

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226 viii) Test turnaround time;

227 ix)  Resources and time available for development, adaptation, evaluation;

228 x)	Intended use (e.g. export, import, surveillance, screening, diagnostic, confirmatory);

229 xi)  Safety ~~factors~~and biocontainment requirements;

230 xii) Customer expectations;

231 xiii) ~~Throughput of test~~Sample numbers and required throughput (automation, robot);

232 xiv) Cost of test, per sample;

233 xv) Availability of reference standards, reference materials and proficiency testing schemes. (See

234 also chapter 2.2.6.).

##### 235 7.2.	Optimisation and standardisation of the test method

236 Once the method has been selected, it must be set up at the laboratory. Additional optimisation is necessary, whether

237 the method was developed in-house (validation) or imported from an outside source (verification). Optimisation

238 establishes critical specifications and performance standards for the test process as used in a specific laboratory.

###### 239 7.2.1. Determinants of optimisation

240 i)	Critical specifications for equipment, instruments consumables, ~~and~~reagents (e.g. chemicals,

241 biologicals), reference standards, reference materials, and internal controls;

242 ii)	Robustness – critical control points and acceptable ranges, attributes or behaviour at critical

243 control points, using statistically acceptable procedures;

244 iii)	Quality control activities necessary to monitor critical control points;

245 iv)	The type, number, range, frequency, and arrangement of test run controls;

246 v)	Criteria for ~~non-subjective~~objective acceptance or rejection of ~~a batch of~~test results;

247 vi)	Criteria for ~~the~~interpretation and reporting of test results;

248 vii)  ~~A~~Documented test method and reporting procedure~~for use by laboratory staff~~;

249 viii) Evidence of technical competence for those ~~who~~performing the test ~~processes~~methods,

250 authorising test results and interpreting results.

##### 251 7.3. Validation of the test method

252 Test method validation evaluates the test for ~~its~~fitness for ~~a given use~~purpose by establishing ~~test~~performance

253 characteristics such as sensitivity, specificity, and isolation rate; and diagnostic parameters such as positive or

254 negative cut-off, repeatability, reproducibility and titre of interest or significance. Validation should be ~~done~~performed

255 using an optimised, documented, and fixed procedure. The extent and depth of the validation process will depend on

256 logistical and risk factors~~. It~~ and may involve any number of activities and amount of data, with subsequent data

257 analysis using appropriate statistical methods (Chapter 1.1.6.). Acknowledging diagnostic test validation science as

258 a key element in the effective detection of infectious diseases, WOAH recently published a Special Issue representing

259 an up-to-date compilation of the relevant standards (WOAH and non-WOAH) and guidance documents for all stages

260 of diagnostic test validation and proficiency testing, including design and analysis, as well as clear, complete and

261 transparent reporting of validation studies in the peer-reviewed literature (Colling & Gardner, 2021). It is important to

262 note that the current version of ISO 17025:2017 specifies that personnel must be authorised to perform validation

263 and related activities, which means that training in validation and verification methods, including results interpretation,

264 is likely to become more important to prove competence (Colling & Gardner, 2021).

###### 265 7.3.1. Activities that validation might include

266 i)	Field or epidemiological studies, including disease outbreak investigations and testing of samples

267 from infected and non-infected animals;

268 ii)	Development  of  testing  algorithms  for  specific  purposes,  e.g.  surveillance,  outbreak

269 investigations, etc.;

270 iii)	Repeat testing in the same laboratory to establish the effect of variables such as operator,

271 reagents, equipment;

272 iv)	Comparison with other, preferably standard methods and with reference standards (if available);

273 v)	Collaborative studies with other laboratories using the same documented method. Ideally

274 organised by a reference laboratory and including testing a panel of samples of undisclosed

275 composition or titre with expert evaluation of results and feedback to ~~the~~participants to estimate

276 reproducibility;

277 vi)	Reproduction of data from an accepted standard method, or from a ~~reputable~~peer-reviewed

278 publication (verification);

279 vii)  Experimental infection ~~or disease outbreak~~ studies;

280 viii) Analysis of internal quality control data.

281 Validation is always a balance between cost, risk, and technical possibilities. There may be cases where

282 ~~quantities such as~~only basic accuracy and precision can ~~only~~be ~~given~~determined, e.g. when the disease is

283 not present in a ~~simplified way~~country or region. Criteria and procedures for the correlation of test results for

284 diagnosis of disease status or for regulatory action must be developed. The criteria and procedures developed

285 should account for screening methods, retesting and confirmatory testing.

286 ~~Test validation is covered in chapter 1.1.6.~~

##### 287 ~~7.4. Uncertainty of the test method~~

288 Statistically relevant numbers of samples from infected and non-infected animals are discussed in chapter 1.1.6. test

289 validation and chapter 2.2.5 statistical approaches to validation.

##### 290 7.4. Estimation of Measurement Uncertainty

291 Measurement ~~of~~ Uncertainty (MU) is “a parameter associated with the result of a measurement that characterises the

292 dispersion of values that could reasonably be attributed to the measure” (Eurachem, 2012). Uncertainty of

293 measurement does not imply doubt about a result but rather increased confidence in its validity. It is not the equivalent

294 to *error*, as it may be applied to all test results derived from a particular procedure.

295 Laboratories must estimate the MU for each test method resulting in a quantitative measurement~~included in their~~

296 ~~scope of accreditation~~, and for any methods used to calibrate equipment, included in their scope of accreditation

297 (ISO/IEC 17025, ~~2005~~2017b).

298 Tests can be broadly divided into two groups: quantitative (e.g. biochemical assays, enzyme-linked immunosorbent

299 assays [ELISA], titrations, real-time polymerase chain reaction [PCR], pathogen enumeration, etc.); and qualitative

300 (bacterial culture, parasite identification, virus isolation, endpoint PCR, immunofluorescence, etc.).

301 The determination of MU is well established in *quantitative*measurement sciences (ANSI, 1997). It may be given as

302 a numeric expression of reliability and is commonly shown as a stated range. Standard deviation (SD) and confidence

303 interval (CI) are examples of the expression of MU, for example the optical density result of an ELISA expressed as

304 ± *n*SD, where *n*is usually 1, 2 or 3. The confidence interval (usually 95%) gives an estimated range in which the

305 result is likely to fall, calculated from a given set of test data. For quantitative measurements, example for a top-down

306 or control-sample approach are provided for an antibody ELISA in chapter 2.2.4, and by the Australian government

307 webpage 28. An example for a quantitative PCR (TaqMan) assay is provided by Newberry & Colling (2021).

308 The ISO/IEC 17025 requirement for “quality control procedures for monitoring the validity of tests” implies that the

309 laboratory must use quality control procedures that cover all major sources of uncertainty. There is no requirement

310 to cover each component separately. Laboratories may establish acceptable specifications, criteria, ranges, etc., at

311 critical control points for each component of the test process. The laboratory can then implement appropriate quality

312 control measures at these critical points, or seek to reduce or eliminate the uncertainty effect of each component.

###### 313 7.4.1. Potential sources of uncertainty include:

314 i)	Sampling;

315 ii)	Contamination;

316 iii)	Sample transport and storage conditions;

317 iv)	Sample processing;

4 Australian Government, Department of Agriculture, Fisheries and Forestry. Worked examples of measurement uncertainty.Measurementuncertainty in veterinary diagnostic testing – DAFF (agriculture.gov.au) (accessed 15 March 2023).

318 v)	Reagent quality, preparation and storage;

319 vi)	Type of reference material;

320 vii)  Volumetric and weight manipulations;

321 viii) Environmental conditions;

322 ix)	Equipment effects;

323 x)	Analyst or operator bias;

324 xi)	Biological variability;

325 xii)  Unknown or random effects.

326 Systematic errors or bias determined by validation must be corrected by changes in the method,

327 adjusted for mathematically, or have the bias noted as part of the report statement.

328 If an adjustment is made to a test or procedure to reduce uncertainty or correct bias then a new

329 source of uncertainty is introduced (the uncertainty of the correction). This must be assessed as part

330 of the MU estimate.

331 The application of the principles of MU to *qualitative*testing is less well defined. The determination

332 and expression of MU has not been standardised for veterinary (or medical, food, or environmental)

333 testing laboratories, but sound guidance exists and as accreditation becomes more important,

334 applications are being developed. The ISO/IEC 17025 standard recognises that some test methods

335 may preclude metrologically and statistically valid calculation of uncertainty of measurement. In such

336 cases the laboratory must attempt to identify and estimate all the components of uncertainty based

337 on knowledge of the performance of the method and making use of previous experience, validation

338 data, internal control results, etc.

339 Many technical organisations and accreditation bodies (e.g. AOAC International, ISO, NATA, A2LA,

340 Standards Council of Canada, UKAS, Eurachem, the Cooperation of International Traceability in

341 Analytical Chemistry) teach courses or provide guidance on MU for laboratories seeking

342 accreditation.

343 ~~The ISO/IEC 17025 requirement for “quality control procedures for monitoring the validity of tests”~~

344 implies that the laboratory must use quality control procedures that cover all major sources of

345 ~~uncertainty. There is no requirement to cover each component separately. Laboratories may~~

346 ~~establish acceptable specifications, criteria, ranges, etc., at critical control points for each component~~

347 ~~of the test process. The laboratory can then implement appropriate quality control measures at these~~

348 ~~critical points, or seek to reduce or eliminate the uncertainty effect of each component. Measurement~~

349 ~~Uncertainty is covered in chapter 2.2.4.~~

###### 350 ~~7.4.1.	Components of tests with sources of uncertainty include:~~

351 i)	Sampling;

352 ~~ii)	Contamination;~~

353 ~~iii)	Sample transport and storage conditions;~~

354 iv)	Sample processing;

355 ~~v)	Reagent quality, preparation and storage;~~

356 ~~vi)	Type of reference material;~~

357 ~~vii)  Volumetric and weight manipulations;~~

358 ~~viii) Environmental conditions;~~

359 ix)	Equipment effects;

360 ~~x)	Analyst or operator bias;~~

361 ~~xi)	Biological variability;~~

362 ~~xii)  Unknown or random effects.~~

363 ~~Systematic errors or bias determined by validation must be corrected by changes in the method,~~

364 ~~adjusted for mathematically, or have the bias noted as part of the report statement.~~

365 ~~If an adjustment is made to a test or procedure to reduce uncertainty or correct bias then a new~~

366 ~~source of uncertainty is introduced (the uncertainty of the correction). This must be assessed as part~~

367 ~~of the MU estimate.~~

368 Additional information on the analysis of uncertainty may be found in the Eurachem Guides to

369 Quantifying Uncertainty in Measurement (Eurachem, 2012) and Use of ~~uncertainty information in~~

370 ~~compliance assessment~~Uncertainty Information in Compliance Assessment (Eurachem, 2007).

##### 371 7.5. Implementation and use of the test method

372 Training should be a planned and structured activity with steps to ensure adequate supervision is maintained while

373 analysts are being trained. Depending on the complexity of the test and the experience of the analyst, training may

374 include any combination of reading and understanding the documented test method, initial demonstration,

375 performance of the test under supervision and independent performance. Analysts should ~~be able to~~demonstrate

376 proficiency in using the test method prior to ~~producing~~being authorised to produce reported results, and on an

377 ongoing basis.

378 The laboratory must be able to demonstrate traceability for all accredited tests and the principle should apply to all

379 tests whether accredited or not. This covers all activities relating to test selection, development, optimisation,

380 standardisation, validation, verification, implementation, reporting, personnel, quality control and quality assurance

381 (see also Section 7.3.1. point vi). Traceability is achieved by using appropriate documented project management,

382 record keeping, data management and archiving systems.

#### 383 8.	Strategic planning

384 Laboratories should have evidence of continual improvement, which is an obligatory requirement for accredited

385 laboratories. The laboratory must ~~be knowledgeable of and stay~~maintain current ~~with~~knowledge of the relevant quality

386 and technical~~management~~ standards and with methods used to demonstrate laboratory competence and establish and

387 maintain technical validity. Evidence of this may ~~be provided by~~include:

388 i)	Attendance at conferences, organisation of in-house or external meetings on diagnostics and quality

389 management;

390 ii)	~~Participation in~~Membership of local and international organisations;

391 iii)	~~Participation in writing~~Contribution to national and international standards (e.g. on ILAC and ISO committees);

392 iv)	Maintenance of current awareness ~~of publications, writing~~through review of and ~~reviewing publications about~~

393 ~~diagnostic methods~~contribution to relevant literature;

394 v)	Participation in training programmes, including visits to other laboratories;

395 vi)	Conducting research;

396 vii)  Participation in cooperative programmes (e.g. Inter-American Institute for Cooperation in Agriculture);

397 viii) Exchange of procedures, methods, reagents, samples, personnel, and ideas;

398 ix)	Planned, continual professional development and technical training;

399 x)	Management reviews;

400 xi)	Analysis of customer feedback;

401 xii)  Root cause analysis of anomalies and implementation of corrective, preventive and improvement actions, as

402 well as effectiveness reviews.

### 403 REFERENCES

404 ANSI (AMERICAN NATIONAL STANDARDS INSTITUTE) (1997). ANSI/NCS 29 Z540-2-1997 (R2012), US Guide to the Expression

405 of Uncertainty in Measurement, First Edition. American National Standards Institute, www.ansi.org.

406 COLLING A.& GARDNER I.A., EDS (2021). Diagnostic test validation science: a key element for effective detection and control

407 of	infectious	animal	diseases.	*Rev.	Sci.	Tech.	Off.	Int.	Epiz.,***40**,	Available	at

408 https://doc.woah.org/dyn/portal/index.xhtml?page=alo&aloId=41245

409 EURACHEM (2007). Eurachem/CITAC Guide: Use of Uncertainty Information in Compliance Assessment, First Edition.

410 Eurachem Secretariat. www.eurachem.org.

411 EURACHEM (2012). Eurachem/CITAC 30 Guide (CG4): Quantifying Uncertainty in Analytical Measurement, Third Edition.

412 Eurachem Secretariat. www.eurachem.org.

413 ISO (2015). ISO 9001:2015. Quality Management Systems – Requirements. International Organization for Standardization

414 (ISO), www.iso.org.

415 ISO/IEC (~~2004a~~2020). ISO/IEC 17000:~~2004~~2020. Conformity Assessment – Vocabulary and General Principles.

416 International Organization for Standardization (ISO), www.iso.org.

417 ISO/IEC (~~2004b~~2017a). ISO/IEC 17011:~~2004~~2 017. Conformity Assessment – General Requirements for accreditation

418 Bodies Accrediting Conformity Assessment Bodies. International Organization for Standardization (ISO), www.iso.org.

419 ISO/IEC (~~2005~~2017b). ISO/IEC 17025:~~2005~~2017. General Requirements for the Competence of Testing and Calibration

420 Laboratories. International Organization for Standardization (ISO), www.iso.org.

421 ISO/IEC (2010). ISO/IEC 17043:2010. Conformity Assessment – General Requirements for Proficiency Testing.

422 International Organization for Standardization (ISO), www.iso.org

423 ISO/IEC (2022~~2012~~). ISO/IEC 15189:~~2012~~2022. Medical Laboratories – Requirements for Quality and Competence.

424 International Organization for Standardization (ISO), www.iso.org

425 JOHNSON P. & CABUANG L. (2021). Proficiency testing and ring trials. *Rev. Sci. Tech. Off. Int. Epiz*., **40**, 189–203.

426 NEWBERRY K. & COLLING A. (2021). Quality standards and guidelines for test validation for infectious diseases in veterinary

427 laboratories. *Rev. Sci. Tech. Off. Int. Epiz*., **40**, 227–237.

428 STEVENSON M., HALPIN K. & HEUER C. (2021). Emerging and endemic zoonotic diseases: surveillance and diagnostics. *Rev.*

429 *Sci. Tech. Off. Int. Epiz.*, **40**, 119–129.

430 WAUGH C. & CLARK G. (2021). Factors affecting test reproducibility among laboratories. *Rev. Sci. Tech. Off. Int. Epiz.,***40**,

431 131–141.

432	*

433	* *

434	NB: FIRST ADOPTED IN 1996 AS *GOOD LABORATORY PRACTICE, QUALITY CONTROL AND QUALITY ASSURANCE*.

435	MOST RECENT UPDATES ADOPTED IN 2017.

5 NCSL: The National Conference of Standards Laboratories.

6 CITAC: The Cooperation of International Traceability in Analytical Chemistry.